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Background: It has been shown that racial/ethnic disparities exist with regard to initiation of and adherence to adjuvant endocrine therapy (AET). However, the relationship among American Indian/Alaska Native (AIAN) individuals is poorly understood, particularly among those who reside in urban areas. We evaluated whether AET initiation and adherence were lower among AIAN individuals than those of other races/ethnicities who were enrolled in the Kaiser Permanente of Northern California (KPNC) health system. Methods: We identified 23,680 patients from the period 1997 to 2014 who were eligible for AET (first primary, stage I‐III, hormone receptor–positive breast cancer) and used KPNC pharmacy records to identify AET prescriptions and refill dates. We assessed AET initiation (≥1 filled prescription within 1 year of diagnosis) and AET adherence (proportion of days covered ≥80%) every year up to 5 years after AET initiation. Results: At the end of the 5‐year follow‐up period, 83% of patients were AET initiators, and 58% were AET adherent. Compared with other races/ethnicities, AIAN women had the second‐lowest rate of AET initiation (non‐Hispanic Black [NHB], 78.0%; AIAN, 78.6%; Hispanic, 83.0%; non‐Hispanic White [NHW], 82.5%; Asian/Pacific Islander [API], 84.7%), the lowest rate of AET adherence after 1 year and 5 years of follow‐up (70.3% and 50.8%, respectively), and the greatest annual decline in AET adherence during the 4‐ to 5‐year period of follow‐up (a 13.8% decrease in AET adherence [from 64.6% to 50.8%]) after initiation of AET. In adjusted multivariable models, AIAN, Hispanic, and NHB women were less likely than NHW women to be AET adherent. At the end of the 5‐year period, total underutilization (combining initiation and adherence) in AET‐eligible patients was greatest among AIAN (70.6%) patients, followed by NHB (69.6%), Hispanic (63.2%), NHW (58.7%), and API (52.3%) patients, underscoring the AET treatment gap. Conclusion: Our results suggest that AET initiation and adherence are particularly low for insured AIAN women. In this study of 23,680 patients who were eligible for adjuvant endocrine therapy (AET), American Indian/Alaska Native (AIAN) women had the lowest AET adherence by the end of the 5‐year study period, and total underutilization (combining initiation and adherence) was greatest among AIAN (70.6%) patients, followed by non‐Hispanic Black (69.6%), Hispanic (63.2%), non‐Hispanic White (58.7%), and Asian/Pacific Islander (52.3%) patients, underscoring the AET treatment gap. [ABSTRACT FROM AUTHOR]

Background: Phosphodiesterase 5A inhibitors (PDEIs), a common treatment for erectile dysfunction, were recently linked to an increased risk of melanoma.Methods: We conducted two parallel case-control studies, using the Danish Nationwide Health Registries (DNHR) and the Kaiser Permanente Northern California (KPNC) electronic health records. Identifying men with histologically verified melanoma (cases) matched on birth year to 10 cancer-free controls, we estimated odds ratios (OR) for melanoma associated with high use of PDEIs (⩾100 tablets filled), adjusting for available confounders.Results: We identified 7045 DNHR and 2972 KPNC cases with invasive melanoma. The adjusted OR for invasive melanoma associated with high PDEI use was 1.22 (95% confidence interval (CI), 0.99-1.49) in DNHR and 0.95 (95% CI, 0.78-1.14) in KPNC. Odds ratios were highest for localised invasive melanoma in DNHR (OR, 1.21) and melanoma in situ in KPNC (OR, 1.15), and lowest for non-localised disease in both populations (ORs 0.75 and 0.61, respectively). The increased ORs were slightly attenuated upon adjustment for markers of health-care utilisation.Conclusions: We found little evidence for a causal association between PDEI use and risk of melanoma. The marginally increased risk of early stage disease likely resulted from more frequent health-care contacts among PDEI users. [ABSTRACT FROM AUTHOR]

Background: Full-field digital mammography (FFDM) has largely replaced film-screen mammography in the US. Breast density assessed from film mammograms is strongly associated with breast cancer risk, but data are limited for processed FFDM images used for clinical care.Methods: We conducted a case-control study nested among non-Hispanic white female participants of the Research Program in Genes, Environment and Health of Kaiser Permanente Northern California who were aged 40 to 74 years and had screening mammograms acquired on Hologic FFDM machines. Cases (n = 297) were women with a first invasive breast cancer diagnosed after a screening FFDM. For each case, up to five controls (n = 1149) were selected, matched on age and year of FFDM and image batch number, and who were still under follow-up and without a history of breast cancer at the age of diagnosis of the matched case. Percent density (PD) and dense area (DA) were assessed by a radiological technologist using Cumulus. Conditional logistic regression was used to estimate odds ratios (ORs) for breast cancer associated with PD and DA, modeled continuously in standard deviation (SD) increments and categorically in quintiles, after adjusting for body mass index, parity, first-degree family history of breast cancer, breast area, and menopausal hormone use.Results: Median intra-reader reproducibility was high with a Pearson's r of 0.956 (range 0.902 to 0.983) for replicate PD measurements across 23 image batches. The overall mean was 20.02 (SD, 14.61) for PD and 27.63 cm(2) (18.22 cm(2)) for DA. The adjusted ORs for breast cancer associated with each SD increment were 1.70 (95 % confidence interval, 1.41-2.04) for PD, and 1.54 (1.34-1.77) for DA. The adjusted ORs for each quintile were: 1.00 (ref.), 1.49 (0.91-2.45), 2.57 (1.54-4.30), 3.22 (1.91-5.43), 4.88 (2.78-8.55) for PD, and 1.00 (ref.), 1.43 (0.85-2.40), 2.53 (1.53-4.19), 2.85 (1.73-4.69), 3.48 (2.14-5.65) for DA.Conclusions: PD and DA measured using Cumulus on processed FFDM images are positively associated with breast cancer risk, with similar magnitudes of association as previously reported for film-screen mammograms. Processed digital mammograms acquired for routine clinical care in a general practice setting are suitable for breast density and cancer research. [ABSTRACT FROM AUTHOR]

Purpose: To examine the association of gain-of-function (GOF) and non-gain-of-function (non-GOF) TP53 mutations with prognosis of metastatic right-sided (RCC) versus left-sided colorectal cancer (LCC)., Methods: This cohort study included patients with metastatic colorectal cancer (CRC) who had next-generation sequencing performed from November 2017 to January 2021. We defined R175H, R248W, R248Q, R249S, R273H, R273L, and R282W as GOF and all other mutp53 as non-GOF. We used Cox regression modeling to examine the association between GOF and non-GOF mutp53 and overall survival (OS), adjusting for age, sex, ethnicity, performance status, Charlson comorbidity index and receipt of chemotherapy., Results: Of total 1,043 patients, 735 had tumors with mutp53 and 308 had wild-type p53 (wtp53). GOF was associated with worse OS than non-GOF mutp53 only in LCC (hazard ratio [HR] = 1.66 [95% CI, 1.20 to 2.29]), but not in RCC (HR = 0.79 [95% CI, 0.49 to 1.26]). Importantly, RCC was associated with worse OS than LCC only in the subset of patients whose CRC carried non-GOF (HR = 1.76 [95% CI, 1.30 to 2.39]), but not GOF mutp53 (HR = 0.92 [95% CI, 0.55 to 1.53]) or wtp53 (HR = 0.88 [95% CI, 0.60 to 1.28]). These associations were largely unchanged after also adjusting for RAS, BRAF, and PIK3CA mutations, and microsatellite instability-high., Conclusion: Poorer survival of patients with metastatic RCC versus LCC appeared to be restricted to the subset with non-GOF mutp53, whereas GOF versus non-GOF mutp53 was associated with poorer survival only among patients with LCC. This approach of collectively classifying mutp53 into GOF and non-GOF provides new insight for prognostic stratification and for understanding the mechanism of sidedness-dependent prognosis. If confirmed, future CRC clinical trials may benefit from incorporating this approach., Competing Interests: Stacey AlexeeffEmployment: The Permanente Medical Group Wenwei HuPatents, Royalties, Other Intellectual Property: A patent application has been submitted (PCT/US20/20141). Title: LIF therapy for inducing intestinal epithelial cell regenerationNo other potential conflicts of interest were reported.

Purpose: Reports suggest that up to 50% of women with hormone receptor-positive (HR+) breast cancer (BC) do not complete the recommended 5 years of adjuvant endocrine therapy (AET). We examined the impact of an outreach program at Kaiser Permanente Northern California (KPNC) on adherence and discontinuation of AET among patients who initiated AET., Methods: We assembled a retrospective cohort of all KPNC patients diagnosed with HR+, stage I-III BC initiating AET before (n = 4287) and after (n = 3580) implementation of the outreach program. We compared adherence proportions and discontinuation rates before and after program implementation, both crude and adjusted for age, race/ethnicity, education, income, and stage. We conducted a pooled analysis of data from six Cancer Research Network (CRN) sites that had not implemented programs for improving AET adherence, using identical methods and time periods, to assess possible secular trends., Results: In the pre-outreach period, estimated adherence in years 1, 2, and 3 following AET initiation was 75.2%, 71.0%, and 67.3%; following the outreach program, the estimates were 79.4%, 75.6%, and 72.2% (p-values < .0001 for pairwise comparisons). Results were comparable after adjusting for clinical and demographic factors. The estimated cumulative incidence of discontinuation was 0.22 (0.21-0.24) and 0.18 (0.17-0.19) at 3 years for pre- and post-outreach groups (p-value < .0001). We found no evidence of an increase in adherence between the study periods at the CRN sites with no AET adherence program., Conclusion: Adherence and discontinuation after AET initiation improved modestly following implementation of the outreach program.

Context: Epidemiologic analyses of gabapentin use and cancer risk in Kaiser Permanente Northern California were previously carried out in a collaborative study and independently evaluated in a UK database., Objective: To update these epidemiologic analyses with 7.5 more years of follow-up., Design: Case-control analyses using conditional logistic regression to estimate relative risk by odds ratios using the prior collaboration's criteria for identifying positive drug-cancer associations and our more stringent criteria requiring stronger association, lower p values, and evidence of dose response. New associations were reanalyzed with additional control for limited measures of smoking and alcohol use., Main Outcome Measures: Gabapentin-cancer associations., Results: No previously found associations met our stringent criteria, but cancers of the mouth/pharynx, esophagus, liver, and vagina did. All odds ratios for 3 or more and 8 or more prescriptions were moderately reduced by control for smoking and alcohol. Substantial elevations of risk of mouth/pharynx, liver, and vaginal cancers were associated with only 1 prescription dispensed. Sensitivity analyses aimed at possible confounding and other biases did not change our conclusions but did reveal a markedly increased risk of vaginal cancer in gabapentin users with epilepsy compared with users without., Conclusion: The reduced magnitude of relative risk with control for smoking and alcohol use suggests confounding by known risk factors. Biologically implausible elevated risk from just 1 prescription suggests confounding by indication. Either or both of these concerns applies to each of the 4 cancer sites associated with gabapentin use. Updated analyses show little if any evidence for carcinogenic effects of gabapentin.

Purpose: To investigate the implications of a cancer diagnosis on medication adherence for pre-existing comorbid conditions, we explored statin adherence patterns prior to and following a new diagnosis of breast, colorectal, or prostate cancer among a multi-ethnic cohort., Methods: We identified adults enrolled at Kaiser Permanente Northern California who were prevalent statin medication users, newly diagnosed with breast, colorectal, or prostate cancer between 2000 and 2012. Statin adherence was measured using the proportion of days covered (PDC) during the 2-year pre-cancer diagnosis and the 2-year post-cancer diagnosis. Adherence patterns were assessed using generalized estimating equations, for all cancers combined and stratified by cancer type and race/ethnicity, adjusted for demographic, clinical, and tumor characteristics., Results: Among 10,177 cancer patients, statin adherence decreased from pre- to post-cancer diagnosis (adjusted odds ratio (OR adj ):0.91, 95% confidence interval (95% CI):0.88-0.94). Statin adherence decreased from pre- to post-cancer diagnosis among breast (OR adj :0.94, 95% CI:0.90-0.99) and colorectal (OR adj :0.79, 95% CI:0.74-0.85) cancer patients. No difference in adherence was observed among prostate cancer patients (OR adj :1.01, 95% CI:0.97-1.05). Prior to cancer diagnosis, adherence to statins was generally higher among non-Hispanic whites and multi-race patients than other groups. However, statin adherence after diagnosis decreased only among these two populations (OR adj :0.85, 95% CI:0.85-0.92 and OR adj :0.86, 95% CI:0.76-0.97), respectively., Conclusions: We found substantial variation in statin medication adherence following diagnosis by cancer type and race/ethnicity among a large cohort of prevalent statin users in an integrated health care setting., Implications for Cancer Survivors: Improving our understanding of comorbidity management and polypharmacy across diverse cancer patient populations is warranted to develop tailored interventions that improve medication adherence and reduce disparities in health outcomes.

Background: Several epidemiologic studies have reported strong inverse associations between metformin use and risk of colorectal cancer, although time-related biases, such as immortal time bias, may in part explain these findings. We reexamined this association using methods to minimize these biases. Methods: A cohort study was conducted among 47,351 members of Kaiser Permanente Northern California with diabetes and no history of cancer or metformin use. Follow-up for incident colorectal cancer occurred from January 1, 1997, until June 30, 2012. Cox regression was used to calculate HRs and 95% confidence intervals (CIs) for colorectal cancer risk associated with metformin use (ever use, total duration, recency of use, and cumulative dose). Results: No association was observed between ever use of metformin and colorectal cancer risk (HR, 0.90; 95% CI, 0.76-1.07) and there was no consistent pattern of decreasing risk with increasing total duration, dose, or recency of use. However, long-term use (≥5.0 years) appeared to be associated with reduced risk of colorectal cancer in the full population (HR, 0.78; 95% CI, 0.60-1.02), among current users (HR, 0.78; 95% CI, 0.59-1.04), and in men (HR, 0.65; 95% CI, 0.45-0.94) but not in women. Higher cumulative doses of metformin were associated with reduced risk. In initial users of sulfonylureas, switching to or adding metformin was also associated with decreased colorectal cancer risk. Conclusions: Our findings showed an inverse association between long-term use of metformin and colorectal cancer risk. Findings, especially the risk reduction among men, need to be confirmed in large, well-conducted studies. Impact: If our findings are confirmed, metformin may have a role in the chemoprevention of colorectal cancer. Cancer Epidemiol Biomarkers Prev; 27(5); 525-30. ©2018 AACR See related commentary by Jackson and García-Albéniz, p. 520 ., (©2018 American Association for Cancer Research.)

Purpose: Re-examine association of fluoxetine and paroxetine with risk of testicular cancer noted in drug screening, with 4 years more follow-up and expanded study of these and other antidepressant drugs., Methods: In the Kaiser Permanente Medical Care Program in Northern California, 906 men with testicular cancer diagnosed August 1996-December 2010 were compared with 38,253 matched controls with race/ethnicity recorded regarding receipt of antidepressant drugs at least 2 years before diagnosis or control index date. Analyses emphasized duration of use and histological subgroups., Results: With control for race/ethnicity and use of other antidepressant drugs, odds ratios (OR) and 95 % confidence intervals (CI) for associations with testicular cancer were as follows: fluoxetine 1.22 (0.88-1.71), paroxetine 1.19 (0.78-1.83), and 1.21 (0.92-1.58) for all serotonin reuptake inhibitors. There was no statistically significant association with risk of all testicular cancers or their histological subtypes for any individual drug or for tricyclics or all antidepressants combined except for citalopram with all testicular cancers 2.55 (1.43-4.52) and those of mixed histology 4.36 (1.50-12.68) and nefazodone with embryonal cancers 9.79 (1.85-51.81). These could readily be chance findings in the context of the many analyses that were performed. Duration of use was not associated with risk of the drugs and drug groups with sufficient numbers of exposed cases for analysis., Conclusions: We found little evidence to support a testicular carcinogenic effect of fluoxetine, paroxetine, or other antidepressant drugs, but a weakly positive association is not ruled out. The signals in prior screening may have been due to chance and/or uncontrolled confounding.

Purpose: The optimal method to assess human epidermal growth factor receptor 2 (HER2) status remains highly controversial. Before reporting patient HER2 results, American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines mandate that laboratories demonstrate ≥ 95% concordance to another approved laboratory or methodology. Here, we compare central laboratory HER2 assessed by fluorescence in situ hybridization (FISH) and quantitative reverse transcriptase polymerase chain reaction (RT-PCR) using Oncotype DX in lymph node-negative, chemotherapy-untreated patients from a large Kaiser Permanente case-control study., Patients and Methods: Breast cancer specimens from the Kaiser-Genomic Health study were examined. Central FISH assessment of HER2 amplification and polysomy 17 was conducted by PhenoPath Laboratories (ratios > 2.2, 1.8 to 2.2, and < 1.8 define HER2 positive, HER2 equivocal, and HER2 negative, respectively). HER2 expression by RT-PCR was conducted using Oncotype DX by Genomic Health (normalized expression units ≥ 11.5, 10.7 to < 11.5, and < 10.7 define HER2 positive, HER2 equivocal, and HER2 negative, respectively). Concordance analyses followed ASCO/CAP guidelines., Results: HER2 concordance by central FISH and central RT-PCR was 97% (95% CI, 96% to 99%). Twelve percent (67 of 568 patients) and 11% (60 of 568 patients) of patients were HER2 positive by RT-PCR and FISH, respectively. HER2-positive patients had increased odds of dying from breast cancer compared with HER2-negative patients. Polysomy 17 was demonstrated in 12.5% of all patients and 33% of FISH-positive patients. Nineteen of 20 FISH-positive patients with polysomy 17 were also RT-PCR HER2 positive. Although not statistically significantly different, HER2-positive/polysomy 17 patients tended to have the worst prognosis, followed by HER2-positive/eusomic, HER2-negative/polysomy 17, and HER2-negative/eusomic patients., Conclusion: There is a high degree of concordance between central FISH and quantitative RT-PCR using Oncotype DX for HER2 status, and the assay warrants additional study in a trastuzumab-treated population.

Objective: To examine whether use of adjuvant therapy varies by race/ethnicity among patients with ductal carcinoma in situ (DCIS) at 3 integrated health plan delivery sites based in California and Massachusetts., Study Design: Cross-sectional study nested within a cohort of women diagnosed as having DCIS between 1990 and 2001., Methods: We reviewed medical records of 3000 non-Hispanic white (69%), black (10%), Hispanic (9%), and Asian or Pacific Islander (12%) women diagnosed as having DCIS between 1990 and 2001 and treated with breast-conserving therapy. chi(2) Test and multinomial logistic regression analysis were used to examine the association between race/ethnicity and use of adjuvant treatments after controlling for patient and clinical variables, including certain pathologic factors., Results: We found no significant differences in DCIS adjuvant treatment among racial/ethnic groups in bivariate or multinomial analyses after adjusting for demographic characteristics, comorbidity, and clinical factors. Minority women were as likely to undergo adjuvant radiation therapy as non-Hispanic white women. However, women 70 years or older (odds ratio, 0.40; 95% confidence interval, 0.31-0.51) and women who lived in areas with low geocoded median family income (odds ratio, 0.65; 95% confidence interval, 0.48-0.89) were less likely to receive adjuvant radiation therapy. Tumor size and comedo histologic growth pattern were associated with increased likelihood of receiving radiation therapy., Conclusion: Use of adjuvant therapy by minority women in these managed care plans is similar to that by non-Hispanic white women, although use was less among older women and among women who lived in poorer neighborhoods.